This invention relates to the field of nuclear magnetic resonance (NMR) spectroscopic devices, and more particularly to a small scale NMR spectroscopic apparatus, and a method of spectroscopy such as measurement of a patient""s body fluid glucose levels.
Nuclear magnetic resonance (NMR) spectroscopy is an analytical and diagnostic technique that can be used for structural and quantitative analysis of a compound in a mixture. NMR is based on the nuclear magnetic properties of certain elements and isotopes of those elements. It is a fundamental law of quantum mechanics that nuclei with a nonzero spin will have a magnetic dipole and will thus interact with electromagnetic radiation. The presence or absence of a spin and the nature of the spin is expressed in terms of the spin quantum number (I) of the nucleus, which may be either 0, xc2xd, or integer multiples of xc2xd. The most important group analytically, because it includes 1H present in many compounds of interest, has a nuclear spin quantum number of xc2xd.
In a uniform magnetic field, a nucleus having a spin quantum number of xc2xd may assume two orientations relative to the applied magnetic field. The two orientations have different energies, so that it is possible to induce a nuclear transition, analogous to flipping a bar magnet in a magnetic field, by applying electromagnetic radiation of the appropriate frequency. This nuclear transition, known as resonance, is thus brought on when the correct combination of magnetic field strength and exciting frequency characteristic of the nuclei of interest are applied. After resonance is achieved, the NMR instrument detects a signal, the signal being a function of the nature and amount of a compound in the test sample as well as nuclear magnetic relaxation considerations. Because all nuclei have unique resonances, e.g. approximately 60 megahertz in a 14 kiloGause (1.4 Tesla) field for protons, 1H NMR will only detect compounds having protons. Moreover, because the exact frequency at which a proton resonates within this range is related to its chemical environment, the 1H NMR signal of protons of one compound can generally be distinguished from another, and the integrated intensity of the signal is directly proportional to the amount of the compound of interest. The position of the resonance signal is characterized by its frequency, i.e., the chemical shift, which is usually expressed on a ppm scale relative to the resonance frequency of some standard compound.
A NMR spectrometer generally comprises one or more magnets producing a strong homogenous magnetic field within a test region, a coil to apply the excitation frequency (the transmitter coil), a coil to generate a signal when the nuclei of the test sample resonate (the receiver coil), and a radiofrequency (RF) oscillator to supply A/C current through the transmitter coil. One coil may act as both the transmitter coil and receiver coil if the current is appropriately gated. A transition occurs in the test sample when the RF frequency applied matches the resonance frequency of the nuclei of the compound of interest.
The size and complexity of NMR spectrometers are largely a function of the magnetic field requirements. A typical NMR magnet used for analytical or chemical structural analysis purposes can weigh from a few hundred to as many as 500 kilograms. However, because the strength of the detected resonance signal is proportional to the magnetic field strength raised to the 3/2 power in the test region, it is very important to provide a magnet with the highest field possible as the magnet is scaled down in size. On the other hand, providing a strong magnetic field generally requires larger, higher weight magnets, which typically increases the cost of the spectrometer depending on the type and the weight of materials used. The most expensive, by far, is the permanent magnet material. Thus, the competing factors of spectrometer field strength and magnet cost must be balanced so that the desired signal strength and cost requirements are met. Moreover, the magnetic field produced must be stable and homogeneous within the test region. The magnetic field strength within the test region, and resulting magnet weight, is a function of a number of variables including the type of magnetic materials used, the extent of the suppression of leakage fields, the size of the test area between the magnets and the configuration of the field flux shaping and conducting components.
Diabetes is a disorder of metabolism characterized by lack of insulin effect. One of the pathologies of diabetes is the inability of glucose to enter the body""s cells and be utilized. Due to the severe effects of excessively high or low blood glucose levels, insulin dependent diabetics should measure their blood glucose levels several times a day. However, the most widely used method requires obtaining a blood sample by finger pricking, which is painful and thus may often be neglected by the patient. 1H NMR is a suitable technique for measuring a patient""s glucose level. However, the in vivo 1H NMR spectroscopic analysis of glucose is complicated by the intense signals generated by water and other compounds in the patient""s blood and tissue. A hand held NMR device has been suggested for in vivo measurement of a patient""s blood glucose levels in U.S. Pat. No. 4,875,486 (Rapoport et al.). However, the device described by Rapoport apparently has never been commercialized. It is believed that the device described could not effectively suppress the large signal of water in the body fluid as required for a clinically suitable device.
Therefore, what has been needed is a small NMR spectrometer and method which allows for the measurement of the concentration of a compound, such as glucose, in a patient. The present invention satisfies these and other needs.
The invention is directed to a relatively small, light weight NMR apparatus and a method for the spectroscopic analysis of a compound in a fluid, such as a patient""s body fluid, and particularly the measuring of a patient""s body fluid component, such as glucose, using a radiofrequency (RF) pulse sequence specific for the detection of such component. The term xe2x80x9cbody fluidxe2x80x9d should be understood to include intracellular and extracellular fluids.
The NMR spectroscopic system of the invention includes a magnet assembly suitable for developing a strong uniform magnetic field across a test region and an RF emission system for the application of a variable exciting frequency normal to the uniform field. The magnet assembly generally comprises two permanent magnets facing one another so that the facing surfaces have opposite polarities, a pole cap tapering inwardly on each of the two facing surfaces of the permanent magnets, and a plurality of radially polarized canceling magnets disposed about the permanent magnets and pole caps. A test region and a coil are located in an air gap between the pole cap facing surfaces.
The permanent magnets are formed from high energy material such as neodymium-iron-boron alloy, so that relatively small, light weight magnets can be used which will generate a strong field in the test region. However, the same high energy magnetic potential generating the high magnetic field in the test region also will exist in all parts of the pole caps. This magnetic potential will, therefore, generate extraneous magnetic fields outside the test region that contribute nothing to the NMR signal. These extraneous fields are called leakage fields. If nothing is done to reduce these leakage fields, the size of the high energy permanent magnetic material must be increased to carry them or their effectiveness will be reduced resulting in reduced magnetic field strength. The principal unchecked leakage fields will form barrel shaped patterns from the sides of one pole cap to the other pole cap and lateral fan shaped patterns from both pole caps to the outer housing. Conventional methods of mitigating the effect of such leakage fields result in an extremely large, heavy, and expensive magnet assembly. In the magnet assembly of the invention, auxiliary magnets are added having strength, position and polarization designed to substantially cancel or reduce the principal leakage fields, thereby reducing the total magnetic flux in the circuit. These auxiliary magnets, referred to as canceling magnets, greatly reduce the leakage fields, to maintain the field strength in the test region without a disadvantageous increase in size, weight, and cost of the magnet assembly of the invention.
In addition there is a low reluctance ferromagnetic member, called a yoke, that conducts the field from the back of one of the permanent magnets, around the outside of the permanent magnet and pole piece array, and to the back of the opposite magnet. This forms an enclosed magnetic circuit and provides an extremely low magnetic resistance to flux flow around the magnetic circuit. This normal design feature reduces the magnetic potential required to achieve the proper field in the test region, allowing reduction in the size of the permanent magnets. However, the canceling magnets of the invention allow the radial distance between the yoke and the permanent magnet to be decreased without increasing the leakage flux. The size of the yoke, permanent magnets, and pole caps can be reduced in proportion to the reduction in the leakage fields and, in addition, the yoke can be reduced by the reduction in spacing. Therefore, the canceling magnets of the invention allow the size of the yoke, permanent magnets and pole caps to be decreased substantially. The magnet assembly is provided with a narrow air gap between the opposing permanent magnets/pole caps of approximately 2 cm, and more specifically about 1.9 cm. The leakage ratio, which is the ratio of the field produced to the field directed to the air gap, is a measure of the effectiveness of a magnet assembly at canceling out the leakage fields. The design of these canceling magnets reduces the leakage ration from about 5:1 to better than 2.5:1.
Because the field homogeneity is directly proportional to the ratio of the size of the pole cap face to the air gap width, the small air gap improves the field homogeneity. The face diameter of the pole cap in the invention is reduced, without sacrificing homogeneity in the test region, by providing a raised portion around the tapered pole cap face called a tapered ring shim. The field inhomogeneities normally associated with a smaller pole cap face to gap ratio is reversed by increasing the field further from the center by decreasing the gap in the outer region with the ring shim. To prevent inhomogeneities due to variations in magnetic saturation in the ring shim structure, the corners of the tapered ring shim are curved to reduce the magnetic flux density concentration normally encountered with sharp corners, so that the field is well below saturation. Spatial variations in saturation induction values through the volume in ferromagnetic materials are well known to occur due to differences in processing the raw material and fabricating the parts.
The method of the invention provides for measurement of the concentration of a constituent, such as glucose, in a fluid, such as a patient""s body fluid, using NMR spectroscopy. The method comprises spectral editing in which a RF pulse sequence is used. The RF pulse sequence combines double quantum filtration and glucose specific signal detection to reduce the water signal and selectively stimulate only the desired resonances of glucose, and thereby facilitate resolution of the glucose signal. Unlike methods in which the proton resonances of all the constituents in the sample are obtained, spectral editing minimizes the problem of distinguishing the glucose signal from resonances of other components in the patient""s blood. Pulse sequences for spectral editing rely on the design of RF pulses to elicit specific nuclear spin system behavior. While pulse sequences used for the spectral editing of different compounds may share common features, the appropriate sequence of RF pulses for a given compound of interest must be individually assembled. Thus the pulses for a given compound have a unique center frequency, range of frequencies, and phase, and are separated by precisely timed intervals. A pulse sequence repeated one or more times, known as a pulse sequence scan, improves the signal to noise of the test sample signal.
The pulse sequence of the invention is specific for resonances of glucose protons which are scalar coupled, i.e., nuclei having a through-bond magnetic interaction. Specifically, the RF pulses selectively excite the glucose protons at about 5.4 ppm and a scalar coupled partner of the protons at about 3.6 ppm, although other suitable scalar coupled pairs in glucose may be used alone or in addition to this pair. Thus, because the pulse sequence of the invention irradiates only these coupled resonances of glucose and no others, the overwhelming signals of the protons of water and other components in the blood are greatly minimized or suppressed, and are generally not detected.
In one aspect of the invention, in vivo measurement is made on a patient""s body fluid. When the specific pulse sequence is used in combination with the NMR apparatus of the invention, an effective, accurate, and relatively small lightweight apparatus is provided with which patients can noninvasively measure their body fluid glucose levels at home or elsewhere at their convenience. The measurement is made on a part of the patient, such as a finger. Because the patient""s finger is composed of several tissues, e.g., skin, fat, tendon, muscle, bone, and blood, the glucose signal is from the body fluid of the totality of such tissues, which signal is related to the patient""s blood glucose level.
The invention allows for substantial size and cost reductions in the magnet assembly for NMR spectroscopy. The pulse sequence of the invention selectively detects the desired resonances in glucose, to allow for accurate quantitative measurement of the glucose level in the complex mixture of a patient""s body fluid. The NMR apparatus and method of the invention is therefore extremely useful to diabetics. These and other advantages of the invention will become more apparent from the following detailed description and exemplary figures.